ONC MedChem

✨ Learning Objectives Recap

By the end of this lecture, you should be able to:

1. Explain MOAs of major oncology drug classes (DNA-targeting, microtubule-targeting, kinase inhibitors).

2. Describe how selectivity for cancer vs. healthy cells works.

3. Recognize structural features of drugs that match their mechanisms.

4. Identify biomolecular targets (DNA, proteins, etc.) for each drug class.

🧪 Quick Chemistry Term Refresher (Simplified Juliet-coded Edition 💅)

🧬 Overview: Major Cancer Drug Strategies

Killing cancer cells? Easy.
Killing only cancer cells? That’s the art of oncology.

Here are the 3 main drug strategies 👇

1⃣ Interfering with DNA Replication / Transcription

Rationale: Cancer cells replicate and transcribe more often than healthy cells — their DNA machinery is overworked.
So: If you block DNA unwinding or transcription, you hit them harder than healthy cells.

Drug classes that do this:

• Alkylating agents (e.g., nitrogen mustards)

• Platinum drugs (e.g., cisplatin)

• Intercalators (e.g., doxorubicin)

• Topoisomerase inhibitors (e.g., etoposide)

2⃣ Messing with Microtubule Dynamics

Rationale: Microtubules are essential for cell division (mitosis).
Cancer cells divide way more often → more vulnerable.
So: Drugs that stop microtubule assembly or disassembly freeze them mid-division 🧊.
Drug classes:

• Vinca alkaloids (block tubule formation)

• Taxanes (prevent tubule breakdown)

3⃣ Switching Off Signaling Pathways (Protein Kinase Inhibitors)

Rationale: Cancer cells have growth signals permanently ON.
Blocking those pathways starves them of “grow” signals 🌱.
Healthy cells can tolerate temporary loss of a pathway, but cancer cells can’t.
Examples: Imatinib, Erlotinib, Sunitinib, etc.

💥 Targeting DNA – Alkylation

🧫 In Chemistry:

Alkylation = adding an alkane (hydrocarbon) part to a molecule.
Simple definition → chemical addition of an alkyl group (R–CH₃ etc.).

🧬 In Biology/Medicine:

“Alkylation” means adding any covalent modification (not just pure alkyls) to DNA bases.

Example: DNA Methylation

• Done by DNA methyltransferase enzymes 🧬

• Adds methyl groups to cytosine (C) → suppresses gene transcription

• Balanced methylation is key:

  • Too much (hypermethylation) = silences tumor suppressor genes ❌

  • Too little (hypomethylation) = overexpresses oncogenes ⚠

So, controlling methylation = controlling cancer’s “on/off” switch 🔘.

🧪 DNA Alkylation as Therapy

Before platinum or biologics, mustard gas derivatives were the OG cancer drugs 😵‍💫

Mechanism 🧬:

• Drug activates via intramolecular SN2 reaction → forms a reactive 3-membered aziridinium ring.

• That ring attacks DNA bases (mostly guanine) → causes crosslinking, mutations, and DNA breaks → cancer cell death ☠.

💡 Crosslinking types:

• Intrastrand: within the same DNA strand.

• Interstrand: between two strands — harder to repair, more lethal.

🧬 Nucleic Acid Targets

Both DNA and RNA can be targeted:

• DNA → replication/transcription interference

• Ribosomes (RNA structures) → translation interference

Drugs exploit differences between prokaryotic and eukaryotic ribosomes 🦠 vs 🧫 to achieve selectivity.
Mechanisms:

• Intercalation: slipping between base pairs (e.g., doxorubicin)

• Alkylation: covalent binding (e.g., cyclophosphamide)

• Chain termination: fake nucleotides stop synthesis (e.g., cytarabine)

yess bestie this is such a juicy chemistry section 🔬💅 — let’s break it all down clearly and beautifully Juliet-coded style 🎀✨

🧪 Nitrogen Mustards – Mechanism of Action

🌿 Core Concept

Nitrogen mustards are alkylating agents that attack DNA.
They contain a 2-chloroethyl group that can form a highly reactive aziridinium ion, which then covalently bonds to N7 of guanine in DNA.

⚙ Step-by-Step Mechanism

1⃣ Intramolecular SN2 reaction

• The nitrogen’s lone pair attacks its own carbon bearing the chlorine → kicks out Cl⁻ → forms a three-membered aziridinium ring (super strained, super reactive 🔥).

• Because this is intramolecular (within the same molecule), it happens very fast — much faster than two separate molecules colliding (intermolecular).

2⃣ DNA Attack (the “Hit”)

• The N7 position of guanine in DNA acts as a nucleophile → attacks the aziridinium ring → opens it up → forms a covalent bond to DNA.

• A second alkylation can occur on another base (same or different strand), leading to:
  💥 Intrastrand crosslink (within one DNA strand), or
  💥 Interstrand crosslink (between two strands — most cytotoxic).

🧬 Why the Aziridinium Ion is Key

• It’s an electrophilic intermediate, meaning it’s eager to react with anything electron-rich (like DNA bases).

• Nitrogen’s lone pair can resonate (delocalize), stabilizing this intermediate just enough to make the reaction controllable (not explosively reactive like mustard gas 😭).

💡 Example: BCMA vs. Chlorambucil

🧠 Key takeaway:
Adding an aryl group (like in chlorambucil) slows activation, making it less toxic and longer-lasting — a major pharmacological upgrade!

⚗ Assessment Style Question: “Broambucil”

Correct answers: ✅ B & C

🩶 Mnemonic:

💊 Cyclophosphamide – A Smarter Nitrogen Mustard

Cyclophosphamide is a prodrug — it’s inactive until metabolized by the liver (CYP450 enzymes).

• The nitrogen is less reactive (can’t easily form the aziridinium ring).

• Liver enzymes convert it into a cytotoxic metabolite with the same DNA-alkylating MOA.

• This “prodrug delay” gives better selectivity and tolerability, since activation happens mainly in cancer tissues (which have high enzyme activity).

💡 Therapeutic advantage:
→ safer systemic profile, longer plasma half-life, and less off-target toxicity.

🧬 Nitrogen Mustard Crosslinking Summary

• Activated via intramolecular reaction → aziridinium ion

• Reacts with guanine N7 in DNA

• Forms interstrand crosslinks (most lethal)

• Causes:

  • DNA fragmentation

  • Blocked replication/transcription

  • Mutations (mispaired bases)

  • Apoptosis

🧩 Essentially: the drug “staples” the DNA strands together so they can’t unzip → replication machinery jams → cell death 💀

🧬 DNA Alkylation & Cross-Linking Recap

⚡️ Interstrand Crosslinks

When two DNA strands get covalently bonded together:

• DNA can’t unwind (un-supercoil) 🧵

• DNA can’t replicate or transcribe properly 💥

• This triggers DNA damage repair pathways, especially Base Excision Repair (BER).

💡 But here’s the catch:
Guanine bases (especially positively charged G⁺) are hydrolytically unstable, meaning they can spontaneously degrade or mispair.
So when you alkylate guanine, it becomes a huge red flag 🚩 → DNA repair enzymes flood the area, and the repair process itself often fragments the DNA even more.

🧠 In short:
Crosslinks lock the DNA zipper shut → repair attempts fail → cell death.

💍 Platinum-Based Alkylating Agents

These are not technically mustards, but they behave similarly — they alkylate (bind covalently) to DNA via platinum–nitrogen coordination bonds, mainly at the N7 of guanine.

⚙ Activation & Mechanism

1⃣ Activation Step:

• The platinum complex starts as a neutral molecule with leaving groups (usually Cl⁻ or oxygen-based ligands).

• When it enters the cell, water molecules replace those leaving groups 💧 — this is called aquation.

• This “water-activated” platinum is now highly electrophilic and ready to bind DNA!

2⃣ DNA Binding:

• Platinum binds primarily to guanine N7 bases on the same DNA strand.

• Two guanines on the same strand → intrastrand crosslink 🔗

• Occasionally, across two strands → interstrand crosslink (less common but more toxic).

💫 Key Structural Requirement: Cis vs Trans

Only cis-platinum complexes (like cisplatin) are effective.

• The cis configuration positions the leaving groups next to each other, allowing both to bind adjacent guanines.

• Trans versions can’t crosslink DNA properly → inactive ❌

🌟 The Platinum Trio (and their upgrades)

🧠 Mnemonic:

🧬 What Happens When Cisplatin Binds DNA

After aquation → it replaces two chlorides with water, forming a reactive complex:

💥 DNA binding results in:

1. Intrastrand crosslinks (same strand):

   • DNA bends toward the major groove.

   • Local unwinding/denaturation occurs.

   • Base pairing (Watson–Crick) is destabilized.

   • Shape change = transcription machinery can’t recognize it.

2. Base Excision Repair (BER) tries to fix it, but often fails → DNA damage → apoptosis.

⚗ Experimental Platinum Agents (like Pt103)

Researchers tweak side groups to change selectivity and activity:

So, even small changes to the “non-platinum” part of the molecule drastically alter reactivity and binding patterns ⚙

🧩 Comparison: Nitrogen Mustards vs. Platinum Compounds

💬 Practice Question Breakdown

✅ Answer: D is FALSE

🩶 Reasoning:

• Nitrogen mustards → interstrand crosslinks (between strands).

• Platinum drugs → intrastrand crosslinks (within one strand).

• Everything else (A–C) is true.

🧠 Mini tip:

🌸 Targeting DNA – Intercalating Agents

💡 What Is Intercalation?

Intercalation = when a molecule slides in between stacked base pairs of DNA 🧬
Think of DNA as a layered lasagna 🍝 — intercalators are flat molecules that slip between the layers.

⚙ Key Features

• Planar aromatic molecules (flat fused rings) fit perfectly between base pairs.

• Non-covalent + reversible binding (mainly via π-π stacking and H-bonds).

• This disrupts replication and transcription because DNA can’t unwind properly.

• It also distorts the helical geometry, causing DNA instability.

🧠 Analogy:

💖 DNA Intercalators – Doxorubicin & Daunorubicin

💥 Mechanisms of Action (Multi-Targeted)

1⃣ DNA Intercalation

• The drug’s 4 fused aromatic rings insert between base pairs.

• The sugar ring (daunosamine) sticks out into the major groove, blocking DNA–protein interactions.

• This physically prevents replication and transcription.

2⃣ Topoisomerase II Inhibition

• Doxorubicin and daunorubicin bind to Topo II, freezing it in the “cleaved” state.

• DNA can’t be religated → permanent breaks → cell death ☠.

3⃣ Free Radical Formation (Iron Complexes)

• The quinone group of doxorubicin chelates Fe²⁺, producing reactive oxygen species (•OH radicals).

• These radicals damage DNA, proteins, and membranes.

• 💔 Cardiotoxicity results from oxidative damage to heart tissue (low catalase activity = poor detox of ROS).

🩶 Mnemonic:

🧬 Topoisomerases: The DNA Untanglers

DNA loves to twist — replication makes it supercoiled, knotted, and catenated (linked like spaghetti 🍝).
Topoisomerases are enzymes that cut and rejoin DNA strands to relieve tension during replication/transcription.

🧩 Topoisomerase I Mechanism

1⃣ Cleavage:

• Tyrosine residue on Topo I attacks the DNA backbone → cleaves one strand.

• Energy for this comes from torsional strain (no ATP needed).

2⃣ Rotation/Relaxation:

• DNA unwinds, relieving supercoiling.

3⃣ Re-ligation:

• Topo I reattaches the broken strand → DNA restored.

💊 Topoisomerase I Inhibitors

Key drugs:

• Camptothecin (natural product)

• Topotecan (active drug)

• Irinotecan (prodrug → active metabolite SN-38)

🧠 Mechanistic picture:

• Topo I cuts the strand 🪓

• Camptothecin slides in 😈

• Now DNA can’t reattach (religation blocked) → permanent damage.

💬 Exam tip:
If you see the word “lactone ring opens → inactive”, think Camptothecin analogs (Topo I inhibitors).

🧬 Topoisomerase II Mechanism

Topo II = the “heavy-duty untangler”

• Cuts both DNA strands (double-strand break).

• Passes another intact strand through the break (like threading a needle).

• Re-ligates both strands after unwinding.

• Requires ATP + Mg²⁺.

🧠 Think:

💊 Topoisomerase II Inhibitors

Drugs:

• Etoposide

• Teniposide

Derived from podophyllotoxin (a microtubule poison) — these versions specifically target Topo II.

⚙ Mechanism

1⃣ Binding:

• Drugs form a ternary complex with DNA + Topo II (3 parts: drug, enzyme, DNA).

2⃣ Intercalation:

• They intercalate into DNA (non-covalently).

3⃣ Block Re-ligation:

• When Topo II cuts the strands, the drug freezes the enzyme–DNA complex.

• Re-ligation is blocked → permanent double-strand breaks → cell death.

🧩 Because Topo II is dimeric, you need 2 drug molecules to fully inhibit one enzyme complex.

💥 Topo I vs. Topo II Summary Table

🧠 Concept Link: “Topo Inhibitors = Re-ligation Blockers”

Both Topo I & II inhibitors cause DNA damage by freezing the enzyme mid-cut, leaving DNA stuck in a broken state 🩸

🧠 Mnemonics to Remember

• I for One: Topo I = one cut.

• II for Two: Topo II = two cuts.

• Camps take ONE tent (Camptothecin = Topo I).

• Eto sounds like TWO (Etoposide = Topo II).

🧫 Mitotic Spindle Poisons

🌟 Purpose

During mitosis, microtubules form the spindle apparatus that pulls chromosomes apart.
So—if we jam microtubule dynamics, we freeze the cell mid-division → cell death 🚫🧬

🧩 Microtubule Basics

🧠 Analogy: microtubules are like magnetic Lego rods powered by GTP; when the battery dies (GTP→GDP), the rod falls apart ⚡️

🔬 Tubulin-Targeted Inhibitors

Microtubules have multiple drug-binding pockets.
Depending on where a drug binds, it either stabilizes or destabilizes the polymer.

* = experimental or not widely approved

🧠 Rule of thumb:

🌿 Sources & Structures

🩶 Mnemonic:

⚙ Tyrosine Kinases and Their Inhibitors (TKIs)

🔋 Normal Role

• Kinases transfer a phosphate (PO₄³⁻) from ATP → protein tyrosine residue.

• Phosphatases remove it.

• This phosphorylation toggles signaling pathways that control growth, division, and survival.

Because kinases share similar ATP-binding pockets, designing selective inhibitors is tricky 🎯.

💊 How TKIs Work

• TKIs bind the ATP-binding site of the kinase, preventing ATP from docking.

• Without ATP, kinase = OFF → no phosphorylation → no growth signal.

• Most TKIs contain a purine-like (adenine-mimic) scaffold that nestles where ATP’s adenine would go, plus extensions reaching into adjacent substrate pockets for selectivity.

🧠 Hand-written note meaning:

🧬 BCR-ABL Fusion Kinase & CML (Targeted Therapy Legend!)

📚 Background

• Philadelphia chromosome = translocation between chromosomes 9 & 22.

• Fuses BCR + ABL → constitutively active tyrosine kinase (“always ON”).

• Triggers unchecked proliferation → Chronic Myeloid Leukemia (CML).

💎 Imatinib (Gleevec)

• First T-targeted “magic bullet.”

• Competitively binds the ATP-site of BCR-ABL, turning it OFF.

• Dramatically improves CML survival.

Resistance Mechanisms

• Mutations in BCR-ABL reduce binding.

• Altered drug uptake or increased efflux can also contribute.

💊 Next-Generation BCR-ABL Inhibitors

All mimic ATP’s adenine and extend deeper into the binding pocket for specific fit 🔑.

🩶 Mnemonic:

🧠 Wrap-Up Summary

🎀 Big takeaways:

• Cancer cells replicate too fast → every process (be it DNA copying, spindle formation, or signaling) becomes a target.

• “Classic” agents damage DNA; “modern” agents silence the signals.

• Medicinal chemistry tunes reactivity & selectivity to maximize tumor kill with minimal collateral damage 💫